Success of HPV vaccination is now a matter of coverage

In a pair of articles in The Lancet Oncology, Lehtinen and colleagues and Wheeler and colleagues present 4-year end of study data from a trial of a prophylactic human papillomavirus (HPV)-16/-18 vaccine (Cervarix, GlaxoSmithKline) in young women aged 15-25 years. From a public-health perspective, these studies have several important contributions.

The results assure us that among HPV-naive women in the 15—25 year age range, Cervarix has extremely high efficacy against HPV-16/-18-associated persistent infection, CIN2, and CIN3 or worse, the best ethical surrogate endpoint for prospective studies of invasive cervical cancer risk. Combined with other trials of Cervarix and Merck’s quadrivalent Gardasil vaccine against HPV-16/-18/-6/-11,3 the evidence is strong for near 100% prophylactic vaccine efficacy in HPV-naive women at any age.

Nonetheless, even with vaccine efficacy near 100% in HPV-naive women, the efficacy in the total vaccinated cohort decreased steeply with increasing age, showing an absence of therapeutic effect against already-acquired infections and associated lesions. We know from natural history studies that new HPV transmission (incidence, not prevalence) decreases with age in most cultures.4 Together, natural history data and results of trials for both vaccines suggest that vaccination before sexual debut, or around the time of menarche, will achieve the greatest reduction in cervical cancer rates.

The 4-year trial data shows no decline in vaccine efficacy in HPV-naive women with time since vaccination.1 We know from other trials of the two vaccines that the duration of protection is several years longer than that shown in the present trial.5 Sustained increased antibody titres and absence of breakthrough HPV-16/-18 outcomes in progressively longer follow-up of vaccinated cohorts are encouraging signs; even without boosters, protection for 10—15 years after primary immunization would prevent HPV-16/-18 infection at its peak incidence, lead to a sharp reduction in the secondary peak incidence of precancers, and eventually provide a proportional reduction in cancer. Life-long immunity is not a requirement for vaccine success, in view of the typically long latency between HPV acquisition and cancer outcome. With current vaccines administered at perimenarche, protection against HPV infection might last long enough to prevent most cervical cancers in that birth cohort.

The substantial cross-protection Cervarix provides against some other oncogenic types, especially against HPV-31/-33/-45, increases its effectiveness for prevention of pre-cancer and cancer, beyond the more limited cross-protection reported for Gardasil. The optimistic predictions about HPV vaccination are confirmed: we now know that Cervarix and Gardasil can have substantial public-health benefit. High coverage with Cervarix or Gardasil vaccination would probably prevent a substantial numbers of cancers, as the investigators note for Cervarix. Data from randomised trials and post-licensure monitoring support decisions by public-health agencies that both vaccines are generally safe and effective, although more extensive safety data to rule out rare or late adverse events are needed and pending. Either vaccine will likely not only prevent cervical cancer, but also a substantial proportion of vulvar and vaginal cancer, anal cancer,6 and possibly oropharyngeal cancer.

Now that Cervarix and Gardasil are proven effective, licensed, and in broad use, what remaining HPV-vaccine-related public health questions are most important? The choice of vaccine might be more of a commercial battle than a crucial public-health issue. The two vaccines are slightly different in preparation and activity. On the one hand, possibly because of its novel adjuvant, Cervarix shows increased cross-protection and generates higher antibody titres than Gardasil after vaccination. We are not sure whether higher titres immediately after vaccination lead to longer duration of protection, and do not know if cross-protection will last as long as protection against the targeted HPV types. On the other hand, Gardasil provides important population coverage against genital warts. Both vaccines are beneficial and it is difficult to decide between them. Universal uptake of vaccination with Cervarix, the present version of Gardasil, or a nine-type version of Gardasil that is in final trials, which protects against seven oncogenic types (HPV-16/-18/-31/-33/-35/-52/-58) plus HPV-6/-11, would likely prevent more than two-thirds of cervical cancers.

Accordingly, we believe that increasing coverage, particularly of sexually-naive adolescent females, is now the most important public-health issue in HPV vaccine efforts. Based on the aggregate data, including those presented by Lehtinen and colleagues and Wheeler and colleagues, we advocate focusing vaccination efforts in this core population to reduce cervical (and other) cancers. The irrefutable public-health benefit from a concerted effort to vaccinate adolescent females need not await resolution of contentious questions of whether to initiate catch-up or mid-adult female vaccination, or a decision on whether Gardasil is cost-effective for adolescent males, among whom vaccination might reduce HPV-related oropharyngeal, penile, and anal cancers.

We are particularly concerned about low vaccination rates in areas where cervical cancer incidence and mortality are high because of inadequate alternative prevention through effective cervical screening, and where nine of 10 cervical cancer deaths occur. Needed new developments that would promote vaccine coverage in these areas, and globally, include an inexpensive HPV vaccine, a formulation that does not require a cold chain to keep the vaccine frozen until administration, or a vaccine that requires only a single dose. The current vaccines are too expensive and difficult to deliver for many low-resource regions. Based on strong immunogenicity in younger adolescents, some regions in Canada and Mexico have decided to administer only two doses of vaccine, with plans to evaluate ongoing efficacy 5—10 years later. New evidence suggests that two doses of Cervarix provide adequate protection against HPV-16/-18 for at least 4 years; comparable data for Gardasil have not yet been presented.

Long-term proof of the safety of HPV vaccines is a public-health priority; uptake will increase as public trust in vaccine safety increases. One safety issue that would benefit from more data (currently being collected) is whether there is any link between vaccination during early pregnancy and miscarriage.
The exciting proof-of-principle phase of vaccine development is over. The practical aspects of vaccine uptake are now the most important issue in HPV vaccine research from a public-health perspective. Increasing uptake through further technological refinements and adaptations to regional circumstances will be the most effective ways to achieve wide-scale high coverage and fulfill the promise of HPV vaccination.This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.